ACS Chem Biol. 2012 Jun 15;7(6):973-7. doi: 10.1021/cb200544u. Epub 2012 Mar 23.
Pursuit of the actinomycete pyrrolobenzodiazepine natural product sibiromycin as a chemotherapeutic agent has been limited by its cardiotoxicity. Among pyrrolobenzodiazepines, cardiotoxicity is associated with hydroxylation at position 9. Deletion of the methyltransferase gene sibL abolishes the production of sibiromycin. Supplementation of growth media with 4-methylanthranilic acid can substitute for its native 3-hydroxy congener. Cultures grown in this fashion yielded 9-deoxysibiromycin. In this study, we characterize the structure and biological activity of sibiromycin and 9-deoxysibiromycin methyl carbinolamines. Preliminary in vitro evidence suggests that 9-deoxysibiromycin exhibits reduced cardiotoxicity while gaining antitumor activity. These results strongly support further exploration of the production and evaluation of monomeric and dimeric glycosylated pyrrolobenzodiazepine analogues of sibiromycin.
作为一种化疗药物，放线菌吡咯并苯并二氮杂卓天然产物西博霉素的研究一直受到其心脏毒性的限制。在吡咯并苯并二氮杂卓中，心脏毒性与 9 位的羟化作用有关。甲基转移酶基因 sibL 的缺失会导致西博霉素的产生减少。在生长培养基中添加 4-甲基邻氨基苯甲酸可以替代其天然的 3-羟基同系物。以这种方式培养的细胞产生了 9-去氧西博霉素。在这项研究中，我们对西博霉素和 9-去氧西博霉素甲醚胺的结构和生物学活性进行了表征。初步的体外证据表明，9-去氧西博霉素的心脏毒性降低，同时抗肿瘤活性增强。这些结果有力地支持了进一步探索西博霉素的单体和二聚体糖基化吡咯并苯并二氮杂卓类似物的生产和评估。
